Injection of an agent into cutaneous and muscle tissues through a needle prick disrupts mechanical and chemical stability of the tissue and initiates a series of electrophysiological and biochemical cascade in the local tissue environment and in free nerve endings of nociceptive primary afferent nerve fibers embedded in the tissue. Cationic channels of the free nerve endings are activated, dependent on biophysical properties of both the needle prick and injected agent. Once voltage gated Na+ channels are activated, membrane depolarization of the nociceptor is propagated, resulting in release of intracellular Ca++. The increase in Ca++ concentration mediates cellular and microenvironmental changes to sensitize nociceptors of the free nerve endings. Furthermore, cells that are disrupted by needle prick could release membrane fatty acids which convert to prostaglandins. Increase in prostaglandins could intensify nociceptive response of the free nerve endings, which translates into intensified painful sensation by a subject.
The majority of the nociceptive signals generated by the free nerve endings are transmitted via both A-delta and C nerve fibers to superficial dorsal horn of the spinal cord. A-delta nerve fibers are responsible for initial sensation of sharp localized pain and C fibers are responsible for so-called second pain of burning and bruised feeling over a wider area than perceived by the A-delta fibers. A-delta fibers are known to be sensitized by intense heat, and high intensity and prolonged activation of C fibers are known to perpetuate the sensitization cycle of C fibers by producing ligands acting on release of pro-inflammatory molecules. At the spinal cord, both A-delta and C-fibers produce glutamate that is a key molecule for transmission of sensation of pain. Postsynaptic nociceptive input then travels upward from the spinal cord to various parts of brain.
There are inhibitory neuronal signals arising from various parts of the brain that descend in the spinal cord to modulate nociception. Descending inhibitory signals may be activated by external factors including stimulation on peripheral or central nervous system. In addition, there are ascending inhibitory signals, albeit minor, arising from parts of the brain. Descending inhibitory signals come to various neuronal structures of the dorsal horn of the spinal cord where downward postsynaptic changes inhibit nociceptive responses. It is believed that in human subjects the descending inhibitory signals can be physically activated by acupuncture, transcutaneous electric nerve simulation (TENS), vibration, dorsal column stimulation and deep brain stimulation.
Vibration is one of peripheral stimulation methods to reduce nociception, which include TENS, acupuncture, acupuncture-like TENS, electroacupuncture and acupressure. Exact mechanisms of analgesia induced by vibration have not been clarified yet but it is believed to be related to activation of A-beta primary afferent nerve fibers that inhibit segmental neurons of the dorsal horn of the spinal cord. It is also proposed that vibration stimulates both high-threshold A-beta fibers and A-delta fibers, which activates the descending inhibitory signals to suppress the dorsal horn neurons. Clinically, both TENS and vibration have been shown to reduce acute and chronic pain conditions, including low back pain, acute orofacial pain, causalgia, pain associated with vaginal delivery of baby and arthritic pain. In particular, vibration of cutaneous tissue of patients has been shown to reduce pain associated with needle prick and injection of agents into the tissue, thereby reducing requirement of anesthetic agents for minor procedures on skin and its appendages.
Various frequencies have been studied for vibration induced analgesia, ranging from 20 Hz to 300 Hz with a varying degree of effectiveness on analgesia. Additional issues of vibration such as duration, amplitude and effective area and depth under vibration have not been studied for its comparative effectiveness except that it appears that analgesia is achieved best in an area directly under vibration. Shortcomings of vibration are short duration of effects and potential development of tolerance over repetitive uses.
Needle-free injection systems using high-pressure jet-stream have been developed over a few years to reduce discomfort of needle prick necessary for injecting agents into tissue. However, needle-free injection disrupts mechanical and chemical stability of the tissue, which initiates similar electrophysiological and biochemical responses in nociceptive primary afferent nerve fibers to needle-based injection systems. Diffuse but limited dispersion from a site of entry of pressured jet-stream of the needle-free system inside the tissue along a longitudinal injection path may be the only advantage of the needle-free system to the needle-based system that produces a radially globular expansion of an injected agent from a tip of a needle inserted in the tissue. It is conceivable that globular expansion of the injected agent, compared to the longitudinally diffuse dispersion of the agent, may exert a more outward pressure per an area of the tissue, thereby disrupting a larger amount of mechanical connection of the tissue. However, one major drawback of the needle-free injection system is a risk of contamination of injection nozzle by recipient's tissue fluid that may emanate from an entry site of injection of the recipient. Unless each device is used only once for each recipient, it poses a significant hazard of transmission of potentially infectious agents such as hepatitis virus or human immunodeficiency virus (HIV) to other recipients receiving injection using the same device. Disposable needle-free injection systems would be available yet their cost-effectiveness cannot be compared favorably to simple disposable syringes and steel needles.
Intensity of nociception, i.e., pain sensation, associated with conventional hypodermic injection of an agent may be ameliorated by limiting extent of mechanical and chemical disruption of a target tissue and by activating descending inhibitory signals. Thinner and shorter hypodermic needles with a more acute angle of bevel may reduce the extent of mechanical disruption of the tissue. Stimulation of an injection site by vibration is one of available methods to activate the descending inhibitory signals. Successful implementation of vibration for achieving analgesia during the needle-based injection would require generation of a vibration field surrounding both a needle penetration site and a tissue infiltration site of an injected agent for an adequate length of time, adequate and redundant activation of primary afferent nerve fibers and fast diffusion of the injected agent from the tip of a needle to adjacent tissues without forming an outwardly pressured globule of the agent in an isolated area of the tissue. Yet the foremost importance should be given to a reproducible method of fail-safe delivery of an agent to a recipient without a risk of contamination by biologic fluids.